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1.
Cardiovasc Drugs Ther ; 35(3): 521-532, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32651897

RESUMO

PURPOSE: Chronic kidney disease (CKD) associates with inflammatory and prothrombotic phenotypes, resulting in higher cardiovascular risk. Factor Xa displays functions beyond coagulation, exhibiting proinflammatory effects. The aim of the present study was to investigate whether a direct FXa inhibitor protects from the endothelial dysfunction (ED) caused by uremia. METHODS: Macro (HUVEC) and microvascular (HMEC) endothelial cells (ECs) were exposed to serum from uremic patients or healthy donors, in absence and presence of apixaban (60 ng/ml). We evaluated changes in surface VCAM-1 and ICAM-1, intracellular eNOS, reactive oxygen species (ROS), and von Willebrand Factor (VWF) production by immunofluorescence, reactivity of the extracellular matrix (ECM) towards platelets, and intracellular signaling. RESULTS: ECs exposed to uremic serum triggered dysregulation of all the parameters. Presence of apixaban resulted in decreased expression of VCAM-1 (178 ± 14 to 89 ± 2% on HMEC and 324 ± 71 to 142 ± 25% on HUVEC) and ICAM-1 (388 ± 60 to 111 ± 10% on HMEC and 148 ± 9% to 90 ± 7% on HUVEC); increased eNOS (72 ± 8% to 95 ± 10% on HMEC); normalization of ROS levels (173 ± 21 to 114 ± 13% on HMEC and 165 ± 14 to 127 ± 7% on HUVEC); lower production of VWF (168 ± 14 to 92 ± 4% on HMEC and 151 ± 22 to 99 ± 11% on HUVEC); and decreased platelet adhesion onto ECM (134 ± 22 to 93 ± 23% on HMEC and 161 ± 14 to 117 ± 7% on HUVEC). Apixaban inhibited p38MAPK and p42/44 activation in HUVEC (139 ± 15 to 48 ± 15% and 411 ± 66 to 177 ± 57%, respectively) (p < 0.05 vs control for all parameters). CONCLUSION: Anti-FXa strategies, such as apixaban, prevented ED caused by the uremic milieu, exhibiting anti-inflammatory and antioxidant properties and modulating the reactivity of the ECM.


Assuntos
Inibidores do Fator Xa/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Pirazóis/farmacologia , Piridonas/farmacologia , Uremia/fisiopatologia , Células Endoteliais/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Humanos , Inflamação/fisiopatologia , Molécula 1 de Adesão Intercelular/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/efeitos dos fármacos , Fator de von Willebrand/efeitos dos fármacos
2.
J Clin Psychopharmacol ; 39(3): 254-257, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30925498

RESUMO

PURPOSE/BACKGROUND: According to available international clinical guides, tricyclic antidepressants are our first- or second-line treatment of choice for severe unipolar major depression. However, the therapeutic option after an unsuccessful response to a tricyclic antidepressant drug in unipolar major depression is still unclear. METHODS/PROCEDURES: This 10-week randomized open-label study assessed the effectiveness of add-on lithium (adjusted to plasma levels) compared with add-on citalopram (30 mg/d) in 104 severe unipolar major depressive patients after a 10-week unsuccessful imipramine (adjusted to plasma level). Efficacy analyses examined changes in the severity of depression symptoms from baseline visit to endpoint and the comparative remission rate between treatment subgroups. FINDINGS/RESULTS: The randomized sample consisted of 104 imipramine-resistant severe unipolar major depressed patients. Both, the percentage of remitters (40.4% vs 21.1%, P = 0.034) and the mean reduction of the Hamilton Depression Rating Scale score (58.8% vs 42.5%, P = 0.005) were significantly greater in the add-on citalopram subgroup at endpoint visit. IMPLICATIONS/CONCLUSIONS: Although we should be cautious about generalizing these results to patients with a less severe unipolar major episode, results from the present study suggest that add-on citalopram is a very effective treatment option in unipolar major depressive episodes after an unsuccessful imipramine regimen.


Assuntos
Citalopram/administração & dosagem , Transtorno Depressivo Maior/tratamento farmacológico , Imipramina/administração & dosagem , Compostos de Lítio/administração & dosagem , Adulto , Idoso , Antidepressivos/administração & dosagem , Antidepressivos Tricíclicos/administração & dosagem , Transtorno Depressivo Maior/fisiopatologia , Quimioterapia Combinada , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Resultado do Tratamento
3.
J Clin Psychopharmacol ; 39(1): 63-66, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30516574

RESUMO

PURPOSE/BACKGROUND: Newer-generation antidepressants used in monotherapy or in combination with other newer-generation antidepressants or other psychotropic drugs are usually preferred as first- or second-step treatment options in resistant depression. According to our clinical experience, tricyclic antidepressants still are one of our preferred first choices in treatment-resistant moderate to severe unipolar major depressive episodes. METHODS: This 10-week open-design randomized study assessed the effectiveness of switching to imipramine (adjusted to plasma levels) compared with add-on mirtazapine (30 mg/d) for treatment of moderate to severe unipolar major depressive episodes after a 10-week unsuccessful venlafaxine regimen (225-300 mg/d). Efficacy analyses examined the change in depressive symptoms severity from baseline visit to endpoint and the comparative remission rate between treatment subgroups. FINDINGS/RESULTS: The randomized sample consisted of 112 venlafaxine-resistant moderate to severe unipolar major depressed patients. Both the percentage of remitters (71.43% vs 39.28%) and the mean reduction of the Hamilton Depression Rating Scale score (76.94% vs 50.72%) were significantly larger in the imipramine subgroup. IMPLICATIONS/CONCLUSIONS: Even though we should be cautious about generalizing these results to patients with a less severe unipolar major episodes, our study suggest that switching to imipramine is a very effective treatment option in unipolar major depressive episodes after an unsuccessful venlafaxine regimen.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Imipramina/uso terapêutico , Mirtazapina/uso terapêutico , Cloridrato de Venlafaxina/uso terapêutico , Adolescente , Adulto , Idoso , Antidepressivos/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
5.
Sci Rep ; 13(1): 22969, 2023 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-38151494

RESUMO

We evaluated modifications in the hemostatic balance of different concentrations of apixaban (APIX) in 25 healthy donors and 53 patients treated with aspirin (ASA, n = 21), ASA and clopidogrel (ASA + CLOPI, n = 11), or ASA and ticagrelor (ASA + TICA, n = 21). Blood samples from participants were spiked ex vivo with apixaban 0 (APIX0), 40 (APIX40), and 160 ng/mL (APIX160). We assessed the effects of APIX on (1) clot formation, by ROTEM thromboelastometry; (2) thrombin generation primed by platelets; and (3) platelet and fibrin interactions with a thrombogenic surface, in a microfluidic model with circulating blood. APIX caused dose-related prolongations of clotting time with minimal impact on other ROTEM parameters. Thrombin generation was significantly inhibited by APIX160, with ASA + TICA actions showing the strongest inhibition (p < 0.01 vs APIX0). Microfluidic studies showed that APIX160 was more potent at suppressing platelet and fibrin interactions (p < 0.001 vs. APIX0). APIX40 demonstrated a consistent antithrombotic action but with a favorable protective effect on the structural quality of fibrin. APIX potentiated the antithrombotic effects of current antiplatelet regimens. APIX at 40 ng/mL, enhanced the antithrombotic action of single or dual antiplatelet regimens but was more conservative for hemostasis than the 160 ng/mL concentration.


Assuntos
Fibrinolíticos , Trombina , Humanos , Fibrinolíticos/farmacologia , Trombina/farmacologia , Aspirina/farmacologia , Plaquetas , Fibrina/farmacologia , Inibidores da Agregação Plaquetária/farmacologia
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